Institute of Biomedical and Genetic Engineering (IBGE), Islamabad 54000, Pakistan.
Department of Internal Diseases, Medical University of Astana, Astana 010000, Kazakhstan.
Cells. 2023 Sep 29;12(19):2382. doi: 10.3390/cells12192382.
The molecular mechanisms and signal transduction cascades evoked by the activation of aryl hydrocarbon receptor (AhR) are becoming increasingly understandable. AhR is a ligand-activated transcriptional factor that integrates environmental, dietary and metabolic cues for the pleiotropic regulation of a wide variety of mechanisms. AhR mediates transcriptional programming in a ligand-specific, context-specific and cell-type-specific manner. Pioneering cutting-edge research works have provided fascinating new insights into the mechanistic role of AhR-driven downstream signaling in a wide variety of cancers. AhR ligands derived from food, environmental contaminants and intestinal microbiota strategically activated AhR signaling and regulated multiple stages of cancer. Although AhR has classically been viewed and characterized as a ligand-regulated transcriptional factor, its role as a ubiquitin ligase is fascinating. Accordingly, recent evidence has paradigmatically shifted our understanding and urged researchers to drill down deep into these novel and clinically valuable facets of AhR biology. Our rapidly increasing realization related to AhR-mediated regulation of the ubiquitination and proteasomal degradation of different proteins has started to scratch the surface of intriguing mechanisms. Furthermore, AhR and epigenome dynamics have shown previously unprecedented complexity during multiple stages of cancer progression. AhR not only transcriptionally regulated epigenetic-associated molecules, but also worked with epigenetic-modifying enzymes during cancer progression. In this review, we have summarized the findings obtained not only from cell-culture studies, but also from animal models. Different clinical trials are currently being conducted using AhR inhibitors and PD-1 inhibitors (Pembrolizumab and nivolumab), which confirm the linchpin role of AhR-related mechanistic details in cancer progression. Therefore, further studies are required to develop a better comprehension of the many-sided and "diametrically opposed" roles of AhR in the regulation of carcinogenesis and metastatic spread of cancer cells to the secondary organs.
芳基烃受体（AhR）激活所引发的分子机制和信号转导级联正变得越来越明晰。AhR 是一种配体激活的转录因子，它整合了环境、饮食和代谢线索，对多种机制进行多效调节。AhR 以配体特异性、上下文特异性和细胞类型特异性的方式介导转录编程。开创性的前沿研究工作为 AhR 驱动的下游信号在多种癌症中的作用提供了引人入胜的新见解。源自食物、环境污染物和肠道微生物群的 AhR 配体策略性地激活了 AhR 信号，并调节了癌症的多个阶段。虽然 AhR 通常被视为配体调节的转录因子，但其作为泛素连接酶的作用令人着迷。因此，最近的证据已经范式性地改变了我们的理解，并促使研究人员深入研究 AhR 生物学的这些新的和具有临床价值的方面。我们对 AhR 介导的不同蛋白质的泛素化和蛋白酶体降解的调节作用的认识迅速增加，开始揭示出有趣的机制。此外，AhR 和表观基因组动力学在癌症进展的多个阶段表现出前所未有的复杂性。AhR 不仅转录调控表观遗传相关分子，而且在癌症进展过程中与表观遗传修饰酶协同作用。在这篇综述中，我们总结了不仅来自细胞培养研究，而且来自动物模型的研究结果。目前正在进行使用 AhR 抑制剂和 PD-1 抑制剂（Pembrolizumab 和 nivolumab）的不同临床试验，这些试验证实了 AhR 相关机制细节在癌症进展中的关键作用。因此，需要进一步的研究来更好地理解 AhR 在调节致癌作用和癌细胞向次级器官转移的多方面和“截然相反”的作用。
